1-alkyl-2-phenethyl-6-substituted-cyclohexanone-3-compounds and process of preparing same



Patented Feb. 19, 1953 1-ALKYL-2-PHENETHYL-6-SUBSTITUTED- CYCLOHEXANONE-ii-COMPOUNDS AND PROCESS OF PREPARING SAME John A. Hogg, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich, acorpo:

ration of Michigan No Drawing. Application October 18,

Serial No. 251,989

Claims. (01. zec-arafif The present invention relates to novel organic compounds and to a method for the preparation thereof. More specifically, this invention relates to l alkyl-2-(meta-substituted-phenethyl)-6- substituted-cyclohexanone-3 compounds and to a method for the preparation thereof by the reduction of the corresponding cyclohexenone-3 compounds. The present application is a continuation-in-part of my prior-filedcopending application Serial 774,171, filed September 15, 1947, now United States Patent'No. 2,582,252.

balkoxycyclohexene-1-one-3, as with Raney metal, palladium, palladium on charcoal, or like The compounds of the present invention are.

valuable intermediates in the preparation of more complex organic molecules, such as hexahydro-. phanthrene compounds, which are active estrori.

gens. In addition, the compounds ,are useful as plasticizers and in the preparation of synthetic.

resins.

hydrogenation catalysts, with the latter being preferred. While a solvent is not essential, an organic solvent, such as methanol, acetic acid, glacial acetic acid, and especially ethanol may be advantageously employed. The reaction is preferably conducted under a pressure of hydrogen, a hydrogen pressure of about twenty to fifty pounds being suitable. Any suitable temperature between about twenty and eighty degrees centigrade may be employed, with room temperature being entirely satisfactory. The theoretical amount of hydrogen, i. e., one mole, is usually absorbed within a period of about one hour. The v compounds thus produced may be separated ac-' 'cording to conventional procedure, e. g., as by It is an object of the present invention vide a novel group of organic compounds. A further object of the invention is the provision. of a process for the production of the said novel compounds. Additional objectswill becomeapparent to one skilledin the art towhich'this invention pertains.

The compounds of the 'preseht 'inventioh may be represented by the following general formula:

wherein X is selected from methoky and hydroxy, wherein Y isselected from hydrogen a nd"l o'\ y,er.

alkyl, and wherein Z is selectedfrom carbox'yi and carbalkoxy, the, term lowergalkylff includ ing methyl, ethyl, propyl, isopropyljbutyl, amylg hexyl, heptyl, octyl, and like alkyl" radicals.

When the group in the 6-position j'is the carbalkoxy group, such group includes; for example,

the carbomethoxy, carbethoxy, carbopropoxy,

,carboiso'propoxyff carbobutoxy, f *"car'lioamyloxy; carbohexoxy; carboheptoxy,-'carbooctoxy;Garbo-Q benzoxy, and the like? Of the alkyl groups in'the' one position, the methyl group represents the" preferred embodiment, although 10131181 alkyl groups, such as those mentioned above, are also suitable.

The methodrof the pres t invention consists in the catalytic hydrogenation of "a ,selected 1 4 'alkyl 2 (meta-methoizyphenethyl) '-'6-car'" filtering andremoving the solvent, and are usually colorless oils having a fruity odor, convertible by' hydrolysis to the corresponding methoxy acid, or, if desired, convertible to the free meta-hydroxy acid bysaponifying and to the meta-hydroxy acid ester by saponifying and then reesterifying the carboxy group in the six position, as with a diazoalkane, e. g., diazomethane, diazoethane, diazobutane, and the like.

The 1 alkyl-2-(meta-methoxyphenethyl)-6- carbalkoxycyclohexene-l-one-3 compounds used as starting materials for the method of the present invention have the following formula:

fioerbalkoxy 3 OVlower-alkyl G g V wherein the substituents have the values given previously. These compounds are prepared from' an appropriate l-alkyl-S-carbalkoxycyclohexenel-one-3, of the formula: a

wherein Y is selected from hydrogen and loweralkyl, lower-alkyl in both instances includin methyl, ethyl, propyl, isopropyl, butyl, amyl,

hexyl, heptyl, octyl, and the like. Such groups as earbomethoxy, carbethox-y, carbopropoxy, carboisopropox'y," 'carbobutoxy," carbo'amyloxy, car--v densation of formaldehyde with an acetoacetic ester, followed by cyclo'dehydration and subsequent selective decarbalkoxylation using sodium ethoxide. The esterifying group of the aceto acetic ester appears as the alkoxyi' part of the -6 carbalkoxy group in such cas'e, and"tliis:com"- pound, wherein Y is hydrogen, the 0 -1 lower.-

alkyl group is methyl, and the 0-6 group. is: is known as Hagema'nns ester" carbethoxy, [Berichte 26, 876 (1893)]. The use of an aide hyde other than formaldehyde introduces an additional substituent Y, which is'loc'at'ed' atcarbon atom five of the ring. The structure of the aldehyde used determines the group Y, and this is restricted only by the nature of available aldehydes [HOr-ning, Denekas, and Field, J. Org. Chem. 9,547 (1944)]. Y, when other than hy-" dro'gen, is preferably an alkyl group of eight carbon-atoms or less, and may be, for example, methyl, ethyl, propyl, isopropyl,. butyl, amyl, hexyl, heptyl, octyl, and the like.

Variation of the C-1 loWer-a'lkyl group may be accomplished according to the procedure of Man'nich and Fourne'au [Berichte 71,. 90 (1939)]. This" involves" reaction: of a ketone' of wherein X is a halogen atom, preferably bromine, in the presence of a suitable condensing agent, such as an alkali metal amide or alcoholate. These agents may be, for example, sodamide, sodium hydride, sodium, or potassium, with the latter especially suitable. As medium for the condensation, benzene, xylene, an alcohol such as ethanol or tertiary butanol, and like organic solvents are advantageously employed, with tertiary butanol being preferred. The reactants may be heated together at a temperature between about eighty degrees and about 150 degrees centigrade, usually at the reflux temperature of the particular solvent employed, for a period of about six to fifteen hours. Twelve hours is usually sufiicient to allow optimum yields of product. Reaction time will, however, vary with the particular temperature employed and exact nature of the reactants, and shorter or longer periods are sometimes entirely satisfactory. Equimola-r proportions of reactants are usually employed. The resulting 'l-alkyl-z-(meta-methoxyplienethyl) -6-carbalkoxycyclohexene-bone-3 OHaO- compounds are a product of the condensation of the beta-phenethyl halide IV with the 2-position of the cyclohexenone ester I, and may be recovered in conventional manner, e. g., by washing with diluteaciddrying, separating from solvent, and purifying by distillation: orithet like.

The followingexamples are given to illustrate the process and products of the present invention, but are in no way to be construed as limiting.

PREPAKAHON lL-IrZlIETHYDZ M-METHOXYPHEN- srrrrny-oeczmes'rnoxrcroLoHsxEnE-LoNE-El Thirteenpgrams (0.563 mole) of sodium was added portionwise to: 250' milliliters of liquid ammonia containing: 0.2 gram of hydrated ferric nitrate, with cooling only when necessary to facilitate the speed of addition. The mixture wasstirred until the blue color was replaced by gray, whereafter the resulting suspension was cooled in an alcohol-Dry Ice bath, and 102.5 grams (0.563 mole) of Hagemanns ester, 1- methyl-Sfcarbethoxy cyclohexene-i-one- 3, was added asratpitliy as possible with the continued application of the" cooling bath. The deep-red reaction mixture was stirred without cooling for twenty'minutes, and was then cooled again while 300 milliliters of dry toluene and fifty milliliters of'sodiuiir-dried ether were added; The cooling bath was then removed andv the mixture stirred twohoursat room temperature until substantially all of the ammonia had escaped. The reaction vessel was then heated to. boiling, at which point the sumo-derivative appeared as a yellow recipitate.

O'nehundred. and twenty grams (0.563 mole) of m-methoxyphenethyi" bromide was added and the suspension refluxed under a nitrogen atmosphere for eighteen hours. The resulting mixture was washed with dilute. hydrochloric acid andthen withwater; The toluene layer was dried over magnesium sulfate, and the toluene removed under vacuum. After a small forerun, distillation of the residue yielded 102 grams (58 per cent) of the desired product boiling at 180-184 degrees centigrade at 0.3 millimeter of mercury pressure.

Anal. Calc. for CmHnOr: C, 72.2;

Found: C, 71.6; H, 7.41

Fiveand eight-tenths grams (0.148 mole) of potassium was dissolved in milliliters of anhydrous tertiary butanol and 29.0 grams (0.148 mole) of 1,5-dimethyl-fi-carbethoxycyclohexene- 1-one-3 was added thereto. After ten minutes, 31.8 grams (0.148 mole) of m-methoxyphenethyl bromide was added and the mixture refluxed under anatmosphere of nitrogen for twelve hours, at the end of which time the solution was neutral. The butanol was then removed under reduced pressure and the residue treated with water and ether. The ether layer was washed with-water, dried, and the ether distilled. Final distillation yielded 27.7 grams (56.7 per cent) of the desired Lfi-dimethyl-Z-(m-methoxyphenethyl)-6-carbethoxycyclohexene 1 one-3. boiling at 178-195 degrees centigrade at 0.3 millimeter of mercury pressure absolute.

In the same manner as given for Preparation 2, 7.3 grams (0.17 mole) of potassium, 136 milliliters of tertiarybutanol, 38.2 grams (0.17 mole) of l methyl-.5-isopropyl-fi-carbethoxycyclohexene-'1'-one-3, and 36.6 grams (0.17 mole) of mmethoxyphenethyl bromide were refluxed .together for a period of about twelve hours and the desired product, 1-methyl-2-(m-methoxyphenethyl) 5 isopropyl-6-carbethoxycyclohexene-1-one-3, boiling at about 188-210 degrees centigrade at 0.3 millimeter of mercury pressure absolute, isolated from the reaction product. The yield of desired compound was fifty per cent of the theoretical.

Example 1.--1-methyl 2 (meta-methomyphenethyl) -6-carbethomycyclohemanone-3 Thirty-three grams (0.104 mole) of the product from Preparation 1, dissolved in 100 milliliters of 95 per cent ethanol, was hydrogenated under pounds pressure using four grams of palladinized charcoal as catalyst. The theoretical amount of hydrogen was absorbed in 5 minutes. After filtration and removal of solvent, there remained l-methyl-2-(m methoxyphenethyl) -6-carbethoxycyclohexanone-3, a waterwhite oil of fruity odor.

Proof of structure was accomplished as follows: this oil was cooled to about 20 degrees centigrade in an alcohol-Dry Ice bath, and eighty milliliters of concentrated sulfuric acid which had been similarly cooled was added thereto. The viscous contents of the flask were stirred as the temperature was allowed to rise slowly,

with cooling from time to time maintaining the temperature always below about ten degrees centigrade. After twenty minutes of shaking and stirring, the temperature was allowed to rise to twenty degrees centigrade, whereafter the mixture was poured onto a large excess of cracked ice. The total reaction time was thirty minutes. A light-colored gum, 1-methyl-2carbethoxy-7' methoxy 1,23,43,10 hexahydrophenanthrene, separated and was extracted with ether.

The ether was removed and the residue hydrolyzed by refluxing for one hour in 200 milliliters of a six per cent solution of potassium hydroxide in 180 milliliters of 95 per cent ethanol and twenty milliliters of water. The alcohol was then removed under vacuum and diluted with water, the water solution washed with ether and acidified with concentrated hydrochloric acid. The free acid came out as an oil which quickly solidified. There was obtained 18.5 grams per cent) of crude acid, melting at 174-178 degrees centigrade, and two recrystallizations from per cent ethanol raised the melting point to 192-193 degrees centigrade.

By the Kahnt-Doisy method, this compound produces the full estrus response in doses of 22.5 amma.

Anal. Calc. for CI'IHZDOHI C, 75.0; H, 7.35

Found: C, 75.0; H, 7.25

Example 2.1 methyZ-Z- (meta hydromyphenethyl) -6-carbo.rycyclohea:anone-3 Demethylation of the product of Example 1 with 45 per cent hydrobromic acid yields an oil, l-methyl-Z-(meta hydroxyphenethyl) 6 carboxycyclohexanone-3.

Example 3.--1 methyl-Z-(ineta hydromyphenethyl) -6-carbometho:cycyclohemnone-3 A solution of the product from Exampl 2 is dissolved in ether and treated with an excess of ethereal diazomethane. The solvent is removed to yield 1-methyl-2-(meta-hydroxyphenethyl)- fi-carbomethoxycyclohexanone-a.

Gil

6 Example 4.-'- '1,5 dlmethyl 2' (Meta-methoxyphenethyl) '-6-carbethoxycyclohexanmze-3 Fifteen and eight-tenths grams (0.0513 mole) of 1,5-dimethyl-2-(m-methoxyphenethyl) -6-carbethoxycyclohexene-l-one-3 was hydrogenated in ethyl alcohol at .forty pounds of hydrogen pressure using palladium on charcoal (1.5 grams of ten per cent palladium on charcoal) as catalyst. When the theoretical amount of hydrogen was absorbed, the catalyst was removed by filtration to give a residue of 1,5-dimethyl-2-(mmethoxyphenethyl) 6 carbethoxycyclohexa none-3.

Proof of structure was accomplished as follows: the product was cooled to approximately ten degrees centigrade and treated carefully with forty milliliters of concentrated sulfuric acid, the tem perature being maintained below about ten degrees centigrade. This operation demanded onehalf hour, whereafter the temperature of the reaction mixture was allowed to rise to room tem perature for ten minutes and poured on cracked ice. The 1,3-dimethyl-2-carbethoxy-7-methoxy- 1,2,3,4,9,lO-hexahydrophenanthrene separated as a gum and was extracted with ether and, after removal of ether, refluxed for 24 hours in alcohol containing four to five equivalents of potassium hydroxide. Alcohol was removed by distillation, the residue diluted with water, and neutral material removed by ether extraction. Acidification of the aqueous layer produced an oil which solidified rapidly and melted below degrees centigrade. Recrystallization of the crude 1,3 dimethyl 2 carboxy 'I methoxy- 1,2,3,4,9,10-hexahydrophenanthrene from ethanol raised the melting point to 173-1745 degrees centigrade.

Example 5.1,5-dime thyl 2 (meta hydromyphenethyl) 6 carborycy'clohemanone 3 and methyl ester thereof The product from Example 4, is hydrolyzed with hydrobromic acid in acetic acid to produce 1,5-dimethyl 2 (meta hydroxyphenethyD-B- carboxycyclohexanone-B, and this compound treated with an excess of diazomethane in ether. Removal of solvent is productive of the desired compound, 1,5-dimethyl-2-(meta-hydroxyphenethyl) -6-carbomethoxycyclohexanone-3.

Example 6.1 methyl-Z-(meta. methoxyphenethyl) -5-z'sopropyl 6 carbethomycyclohema none-3 In the same manner as given for Example 4, 24.3 grams of 1-methyl-2-(m-methoxyphenethyl) -5-isopropyl 6 carbethoxycyclohexene 1-one-3 was hydrogenated under forty pounds of hydrogen pressure with 2.5 grams of palladium on charcoal catalyst in 100 milliliters of ethanol to produce 1-methyl-2-(m-methoxyphenethyl) s-isopropyl 6 carbethoxycyclohexanone-3. As proof of structure, this compound was cyclized by treatment with 65 milliliters of concentrated sulfuric acid at a temperature below about ten degrees centigrade. Potassium hydroxide (8.75 grams) in '75 milliliters of ethyl alcohol was added to the cyclization product, 1-methyl-2- carbethoxy-S isopropylfl-methoxy 1,2,3,4,9,10- hexahydrophenanthrene, the mixture refluxed and the product worked up as in Example 4. The free acid, after crystallization from methanol, was a white solid melting at about 174 degrees centigrade.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compoundsshown -and 'described, as obvious modifications'and 'equivalents willbeapparout to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I'claim: I

1. A 1 methyI-Z-(ineta-X-phenethyl) -5-Y"-6- Z-cyclohexanone-b of the. formula:

wherein: X is selected from the group consisting of methoxy and hydroxy; Y is selected 'from the group consisting of hydrogen and lower-alkyl; r

and Z is selected from the group consisting of carboxy and carbalkoxy.

2. 1 methyl 2-(meta-methoxyphenethyl) -6- carbethoxycyclohexanone-3.

s. 1,5 dimethyl-Z-(meta-methoxyphenethyl)- wherein: Yis selected; from the group consistin I i I -carbalkoxy [6O- J-Iowcrmikyl wherein Y has the value. given below the previous formula.

6. The process of claim 5, wherein the hydrogenation is with hydrogen and a palladium on charcoal catalyst.

7. The process of claim 5, wherein the hydrogenation is conducted at a temperature between about 20 and 80 degrees centigrade.

8. The process of claim 5, wherein the product is thereafter saponified by reaction with an alcoholic base and neutralized to produce the 6-carboxylic acid.

9. 1 methyl 2-(meta-hyclroxyphenethyl) -6- carboxycyclohexanone-S.

3, 1) -6carboxycyolohexanone-3.

JOHN A. HOG-G.

No references cited. 

1. A 1 - METHYL-2-(META-X-PHENETHY)-5-Y-6 Z-CYCLOHEXANONE-3 OF THE FORMULA:
 5. THE PROCESS WHICH INCLUDES: HYDROGENATING, UNDER A PRESSURE OF HYDROGEN AND WITH A HYDROGENATION CATALYST, THE OLEFINIC DOUBLE BOND OF A COMPOUND OF THE FORMULA: 